Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 2000 Jul;91(7):674–680. doi: 10.1111/j.1349-7006.2000.tb00998.x

Chemopreventive Effects of Coumaperine from Pepper on the Initiation Stage of Chemical Hepatocarcinogenesis in the Rat

Mitsuaki Kitano 1, Hideki Wanibuchi 1, Hiroe Kikuzaki 3, Nobuji Nakatani 3, Susumu Imaoka 2, Yoshihiko Funae 2, Shuji Hayashi 1, Shoji Fukushima 1,✉
PMCID: PMC5926419  PMID: 10920273

Abstract

This study was designed to investigate the chemopreventive action of three natural products, coumaperine, aurapten and an extract from rosemary, against the initiation stage of rat hepatocarcinogenesis. Coumaperine has been isolated from white pepper as a naturally occurring antioxidative agent, but its potential modifying effects on carcinogenesis remain unclear. In experiment 1, a modification of the model developed by Tsuda et al. was applied, with assessment of numbers and areas of induced glutathione S‐transferase placental form (GST‐P)‐positive hepatocellular foci in male F344 rats. Coumaperine, aurapten and the extract from rosemary were administered i.g. at 100 mg/kg/day once daily for 5 days with initiation by diethylnitrosamine (DEN) on day 4 (20 mg/kg, i.p.). Numbers and areas of GST‐P‐positive foci in each group given test chemicals tended to be decreased as compared to the vehicle control group values, significance being achieved for number with coumaperine. Experiment 2 was planned to investigate the mechanism of the inhibitory effects of coumaperine. Livers at 8 h after initiation by DEN were examined with coumaperine administered at 100 mg/kg/day once daily for 3 days. Proliferating cell nuclear antigen (PCNA)‐ positive cells tended to be decreased as compared to the vehicle control, but no effects on apoptosis or cytochrome P‐450 (CYP) 2E1 expression were apparent. Our results suggest that coumaperine provides protection against initiation of hepatocarcinogenesis, and that this is related to inhibition of cell proliferation.

Keywords: Coumaperine, Chemoprevention, Rat hepatocarcinogenesis

Full Text

The Full Text of this article is available as a PDF (177.2 KB).

REFERENCES

  • 1. ) Takada , N. , Yano , Y. , Wanibuchi , H. , Otani , S. and Fukushima , S.S‐Methylcysteine and cysteine are inhibitors of induction of glutathione S‐transferase placental form‐positive foci during initiation and promotion phases of rat hepatocarcinogenesis . Jpn. J. Cancer Res. , 88 , 435 – 442 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. ) Narisawa , T. , Fukaura , Y. , Hasebe , M. , Nomura , S. , Oshima , S. , Sakamoto , H. , Inakuma , T. , Ishiguro , Y. , Takayasu , J. and Nishino , H.Prevention of N‐methylnitrosourea‐induced colon carcinogenesis in F344 rats by lycopene and tomato juice rich in lycopene . Jpn. J. Cancer Res. , 89 , 1003 – 1008 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. ) Kawamori , T. , Lubet , R. , Steele , V. E. , Kelloff , G. J. , Kaskey , R. B. , Rao , C. V. and Reddy , B. S.Chemopreventive effect of curcumin, a naturally occurring anti‐inflammatory agent, during the promotion/progression stages of colon cancer . Cancer Res. , 59 , 597 – 601 ( 1999. ). [PubMed] [Google Scholar]
  • 4. ) Bhide , S. V. , Azuine , M. A. , Lahiri , M. and Telang , N. T.Chemoprevention of mammary tumor virus‐induced and chemical carcinogen‐induced rodent mammary tumors by natural plant products . Breast Cancer Res. Treat. , 30 , 233 – 242 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 5. ) Inatani , R. , Nakatani , N. and Fuwa , H.Structure and synthesis of new phenolic amides from Piper nigrum L . Agric. Biol. Chem. , 45 , 667 – 673 ( 1981. ). [Google Scholar]
  • 6. ) Nakatani , N. , Inatani , R. , Ohta , H. and Nishioka , A.Chemical constituents of peppers (Piper spp.) and application to food preservation: naturally occurring antioxidative compounds . Environ. Health Perspect. , 67 , 135 – 142 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Hirose , M. , Shirai , T. , Takahashi , S. , Ogawa , K. and Ito , N.Organ‐specific modification of carcinogenesis by antioxidants in rats . Basic Life Sci. , 61 , 181 – 188 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Inatani , R. , Nakatani , N. , Fuwa , H. and Seto , H.Structure of a new antioxidative phenolic diterpene isolated from rosemary (Rosmarinus officinalis L.) . Agric. Biol. Chem. , 46 , 1661 – 1666 ( 1982. ). [Google Scholar]
  • 9. ) Nakatani , N. , Yamada , Y. and Fuwa , H.7‐Geranyloxycoumarin from juice oil of hassaku (Citrus hassaku) and antimicrobial effects of related coumarins . Agric. Biol. Chem. , 51 , 419 – 423 ( 1987. ). [Google Scholar]
  • 10. ) Yamada , Y. , Nakatani , N. and Fuwa , H.Epoxyaurapten and marmin from juice oil in hassaku (Citrus hassaku) and the spasmolytic activity of 7‐geranyl‐oxycoumarin‐related compounds . Agric. Biol. Chem. , 51 , 1105 – 1110 ( 1987. ). [Google Scholar]
  • 11. ) Tanaka , T. , Kawabata , K. , Kakumoto , M. , Matsunaga , K. , Mori , H. , Murakami , A. , Kuki , W. , Takahashi , Y. , Yonei , H. , Satoh , K. , Hara , A. , Maeda , M. , Ota , T. , Odashima , S. , Koshimizu , K. and Ohigashi , H.Chemoprevention of 4‐nitroquinoline 1‐oxide‐induced oral carcinogenesis by citrus auraptene in rats . Carcinogenesis , 19 , 425 – 431 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Murakami , A. , Kuki , W. , Takahashi , Y. , Yonei , H. , Nakamura , Y. , Ohto , Y. , Ohigashi , H. and Koshimizu , K.Auraptene, a citrus coumarin, inhibits 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced tumor promotion in ICR mouse skin, possibly through suppression of superoxide generation in leukocytes . Jpn. J. Cancer Res. , 88 , 443 – 452 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Tanaka , T. , Kawabata , K. , Kakumoto , M. , Hara , A. , Murakami , A. , Kuki , W. , Takahashi , Y. , Yonei , H. , Maeda , M. , Ota , T. , Odashima , S. , Yamane , T. , Koshimizu , K. and Ohigashi , H.Citrus auraptene exerts dose‐dependent chemopreventive activity in rat large bowel tumorigenesis: the inhibition correlates with suppression of cell proliferation and lipid peroxidation and with induction of phase II drug‐metabolizing enzymes . Cancer Res. , 58 , 2550 – 2556 ( 1998. ). [PubMed] [Google Scholar]
  • 14. ) Tsuda , H. , Lee , G. and Farber , E.Induction of resistant hepatocytes as a new principle for a possible short‐term in vivo test for carcinogens . Cancer Res. , 40 , 1157 – 1164 ( 1980. ). [PubMed] [Google Scholar]
  • 15. ) Nakatani , N. , Inatani , R. and Fuwa , H.Structure and syntheses of two phenolic amides from Piper nigrum L . Agric. Biol. Chem. , 44 , 2831 – 2836 ( 1980. ). [Google Scholar]
  • 16. ) Hsu , S. M. , Raine , L. and Fanger , H.Use of avidin‐biotinperoxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures . J. Histochem. Cytochem. , 29 , 577 – 580 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Nakajima , M. , Iwata , K. , Yamamoto , T. , Funae , Y. , Yoshida , T. and Kuroiwa , Y.Nicotine metabolism in liver microsomes from rats with acute hepatitis or cirrhosis . Drug Metab. Dispos. , 26 , 36 – 41 ( 1998. ). [PubMed] [Google Scholar]
  • 18. ) Nakano , H. , Hatayama , I. , Satoh , K. , Suzuki , S. , Sato , K. and Tsuchida , S.c‐Jun expression in single cells and preneoplastic foci induced by diethylnitrosamine in B6C3F1 mice: comparison with the expression of pi‐class glutathione S‐transferase . Carcinogenesis , 15 , 1853 – 1857 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 19. ) Gavrieli , Y. , Sherman , Y. and Ben‐Sasson , S. A.Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation . J. Cell Biol. , 119 , 493 – 501 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. ) Chiu , K. Y. , Loke , S. L. and Wong , K. K.Improved silver techique for showing nucleolar organizer regions in paraffin wax sections . J. Clin. Pathol. , 42 , 992 – 994 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Sato , M. , Chida , T. , Watanabe , H. , Noda , Y. , Ajioka , Y. , Katayama , A. and Abe , M.A modified argyrophilic nucleolar organizer region (AgNOR) staining method for nucleolar staining in formalin‐fixed, paraffin‐embedded materials . Gastroenterol. Jpn. , 26 , 391 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Leek , R. D. , Alison , M. R. and Sarraf , C. E.Variations in the occurrence of silver‐staining nucleolar organizer regions (AgNORs) in non‐proliferating and proliferating tissues . J. Pathol. , 165 , 43 – 51 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Lok , E. , Mehta , R. , Jee , P. , Laver , G. , Nera , E. A. , McMullen , E. and Clayson , D. B.The effect of butylated hydroxytoluene on the growth of enzyme‐altered foci in male Fisher 344 rat liver tissue . Carcinogenesis , 16 , 1071 – 1078 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Watanabe , T. , Katsura , Y. and Yoshitake , A.IPAP: image processor for analytical pathology . J. Toxicol. Pathol. , 7 , 353 – 361 ( 1994. ). [Google Scholar]
  • 25. ) Farber , E.Alcohol and other chemicals in the development of hepatocellular carcinoma . Clin. Lab. Med. , 16 , 377 – 394 ( 1996. ). [PubMed] [Google Scholar]
  • 26. ) Rüschoff , J. , Fauser , G. , Knüchel , R. and Hofstädter , F.AgNOR quantification with special reference to staining patterns . Zentralbl. Pathol. , 140 , 23 – 30 ( 1994. ). [PubMed] [Google Scholar]
  • 27. ) Tanaka , T. , Kojima , T. , Kawamori , T. , Wang , A. , Suzuki , M. , Okamoto , K. and Mori , H.Inhibition of 4‐nitroquinone‐1‐oxide‐induced rat tongue carcinogenesis by the naturally occurring plant phenolics caffeic, ellagic, chlorogenic and ferulic acids . Carcinogenesis , 14 , 1321 – 1325 ( 1993. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Rahman , K. M. , Sugie , S. , Okamoto , K. , Watanabe , T. , Tanaka , T. and Mori , H.Modulating effects of diets high in ω‐3 and ω‐6 fatty acids in initiation and postinitiation stages of diethylnitrosamine‐induced hepatocarcinogenesis in rats . Jpn. J. Cancer Res. , 90 , 31 – 39 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. ) Iwata , H. , Otoshi , T. , Takada , N. , Murai , T. , Tamano , S. , Watanabe , T. , Katsura , Y. and Fukushima , S.Validation of silver‐stained nucleolar organizer regions for evaluation of invasive character of urinary bladder carcinoma in rats and mice . Urol. Res. , 23 , 27 – 32 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Ishizuka , M. , Yoshino , S. , Yamamoto , Y. , Yamamoto , H. , Imaoka , S. , Funae , Y. , Masuda , M. , Iwata , H. , Kazusaka , A. and Fujita , S.Isozyme selective alterations of the expression of cytochrome P450 during regeneration of male rat liver following partial hepatectomy . Xenobiotica , 27 , 923 – 931 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Lerche , C. , Jossic , C. L. , Fautrel , A. , Waziers , I. D. , Ballet , F. , Guillouzo , A. and Corcos , L.Rat liver epithelial cells express functional cytochrome P450 2E1 . Carcinogenesis , 17 , 1101 – 1106 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Yamazaki , H. , Oda , Y. , Funae , Y. , Imaoka , S. , Inui , Y. , Guengerich , F. P. and Shimada , T.Participation of rat liver cytochrome P450 2E1 in the activation of N‐nitrosodimethylamine and N‐nitrosodiethylamine to products genotoxic in an acetyltransferase‐overexpressing Salmonella typhimurium strain (NM2009) . Carcinogenesis , 13 , 979 – 985 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Deguchi , T. and Pitot , H. C.Expression of c‐myc in altered hepatic foci induced in rats by various single doses of diethylnitrosamine and promotion by 0.05% phenobarbital . Mol. Carcinog. , 14 , 152 – 159 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Nakae , D. , Mizumoto , Y. , Kobayashi , E. , Noguchi , O. and Konishi , Y.Improved genomic/nuclear DNA extraction for 8‐hydroxydeoxyguanosine analysis of small amounts of rat liver tissue . Cancer Lett. , 97 , 233 – 239 ( 1995. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Suzuki , T. , Imagawa , M. , Yamada , R. , Yokoyama , K. , Kondo , S. , Itakura , K. and Muramatsu , M.Acute changes in liver gene expression in the N‐nitrosodiethylaminetreated rat . Carcinogenesis , 15 , 1759 – 1761 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Tsujiuchi , T. , Tsutsumi , M. , Honoki , K. , Horiguchi , K. , Kobayashi , E. , Denda , A. and Konishi , Y.Effects of novobiocin on the induction of gamma‐glutamyltranspeptidase positive foci in the liver of rats treated with diethylnitrosamine . Exp. Toxicol. Pathol. , 46 , 115 – 118 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 37. ) Feuer , G.Hepatic metabolism and carcinogenesis: its role in hepatoma and adenocarcinoma . Ann. NY Acad. Sci. , 534 , 541 – 551 ( 1988. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES